Menin inhibitors in AML: Where are we now, and where are we going?

During a meeting of the AML Hub Steering Committee, held on February 19, 2026, Jorge Cortes chaired a discussion on the topic, Menin inhibitors in AML: Where are we now, and where are we going? The discussion featured contributions from Charles Craddock, Brian Huntly, and Jeffrey Lancet.

Cortes first outlined the rationale for the use of menin inhibitors in acute myeloid leukemia (AML) and their mechanism of action (Figure 1). He then provided an overview of those in development for the treatment of AML and the latest data from key clinical trials, including updates from the 67th American Society of Hematology (ASH) Annual Meeting and Exposition and the European Hematology Association (EHA) 2025 Congress (Table 1). He concluded by discussing potential future directions for menin inhibition in AML, such as their use earlier in the treatment pathway or in additional molecularly defined AML subsets, and strategies to mitigate differentiation syndrome (Figure 2).

Table 1. Menin inhibitors in AML: An overview of the latest updates from ASH 2025 and EHA 2025

*Treatment-related adverse events. ^†Data reported for the RP2D, 90/100 mg BID. ^‡Data reported for the RP2D, 300 mg BID. ^§Values not available.
AML, acute myeloid leukemia; ASH, American Society of Hematology; Aza, azacitidine; BID, twice daily; CR, complete remission; CRh, CR with partial hematologic recovery; EHA, European Hematology Association; KMT2Ar, KMT2A-rearranged; ND, newly diagnosed; NPM1m, NPM1-mutated; ORR, overall response rate; RP2D, recommended phase II dose; R/R, relapsed/refractory; TEAE, treatment-emergent adverse event; Ven, venetoclax.

Key points

• Potential future directions for menin inhibitors in AML include investigation of existing salvage regimens in the first-line setting, in both fit and unfit patient populations.
• Careful consideration of key challenges in the NPM1-mutated (NPM1m) and KMT2A-rearranged (KMT2Ar) settings will be required when designing trials, to meet regulatory requirements.
  • Randomized controlled trials in NPM1m AML are needed for regulatory approval. However, as current standard therapy already gives favorable outcomes in this patient population, there is a need to demonstrate sufficient benefit with any investigational regimens vs existing regimens, with regard to efficacy, safety, associated costs, and treatment burden.
  • Designing randomized controlled trials for KMT2Ar AML is difficult due to its rarity. The use of historical controls may be acceptable to regulators if a large and clinically meaningful benefit is demonstrated, given the poor prognosis of this population; however, adjusting for allogeneic hematopoietic stem cell transplantation (allo-HSCT) will be an important issue.
• Resistance to menin inhibitors is an ongoing challenge in treating patients with NPM1m or KMT2Ar AML.
  • In cases of genetic resistance, where certain mutations may confer resistance to specific inhibitors, some new agents may be advantageous by inducing degradation of the target protein rather than targeting the gene itself.
  • In the more common instances of non-genetic resistance, which often involves reactivation of leukemogenic programs via alternative epigenetic regulators (e.g. PRC1 complex, KAT6A pathways), more inhibitors targeting these pathways exist, thus offering potential combination regimens as a strategy for mitigating the clinical impact of resistance.
• Careful patient selection for trials investigating triplet regimens is another consideration, as early use of novel triplet regimens could promote resistance and compromise future salvage options.
  • Risk stratification can facilitate identification of patients most likely to benefit when designing early-phase trials.

This educational activity is independently supported by Johnson & Johnson. All content was developed by the faculty in collaboration with SES. Funders were allowed no influence.